Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2022 Jul 12;328(2):151-161.
doi: 10.1001/jama.2022.9805.

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial

David W Oslin  1   2 , Kevin G Lynch  1   2 , Mei-Chiung Shih  3   4 , Erin P Ingram  1 , Laura O Wray  5   6   7 , Sara R Chapman  8 , Henry R Kranzler  1   2 , Joel Gelernter  9   10 , Jeffrey M Pyne  11   12 , Annjanette Stone  11 , Scott L DuVall  13   14   15 , Lisa Soleymani Lehmann  16   17   18 , Michael E Thase  1   2 ; PRIME Care Research Group; Muhammad Aslam  19   20 , Steven L Batki  21   22 , James M Bjork  23   24 , Frederic C Blow  25   26 , Lisa A Brenner  27   28 , Peijun Chen  29   30   31 , Shivan Desai  23 , Eric W Dieperink  32   33 , Scott C Fears  34   35 , Matthew A Fuller  31   36 , Courtney S Goodman  37 , David P Graham  38   39 , Gretchen L Haas  8   40 , Mark B Hamner  41   42 , Amy W Helstrom  1   2 , Robin A Hurley  37   43 , Michael S Icardi  44   45 , George J Jurjus  29   31 , Amy M Kilbourne  46   47 , Julie Kreyenbuhl  48   49 , Daniel J Lache  50   51 , Steven P Lieske  21 , Julie A Lynch  14   52 , Laurence J Meyer  14   53 , Cristina Montalvo  16   54 , Sumitra Muralidhar  46   55 , Michael J Ostacher  56   57 , Gayla Y Paschall  11 , Paul N Pfeiffer  25   26 , Susana Prieto  58 , Ronald M Przygodzki  46 , Mohini Ranganathan  9   59 , Mercedes M Rodriguez-Suarez  58 , Hannah Roggenkamp  34   60 , Steven A Schichman  11   61 , John S Schneeweis  62 , Joseph A Simonetti  27   63   64 , Stuart R Steinhauer  8   40 , Trisha Suppes  56   57 , Maria A Umbert  58 , Jason L Vassy  16   65 , Deepak Voora  66   67 , Ilse R Wiechers  6   68 , Amanda E Wood  69   70
Affiliations
Randomized Controlled Trial

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial

David W Oslin et al. JAMA. .

Abstract

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment.

Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes.

Design, setting, and participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications.

Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978).

Main outcomes and measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters.

Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45).

Conclusions and relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission.

Trial registration: ClinicalTrials.gov Identifier: NCT03170362.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Oslin reported receiving grants from the Department of Veterans Affairs (VA) Office of Research and Development (OR&D) and Janssen Pharmaceuticals, and nonfinancial support from Myriad Genetics during the conduct of the study; Dr Oslin was the co-chair of the VA/Department of Defense Clinical Practice Guideline for Major Depressive Disorder during the study. Dr K. G. Lynch reported receiving grants from the VA OR&D during the conduct of the study, and personal fees from the University of Michigan and Northwell Health outside the submitted work. Dr Shih reported receiving grants from the VA Health Services Research and Development (HSR&D) and is an employee at the VA Cooperative Studies Program. Her work on this study was supported by the Merit Review Award from the VA HSR&D. Dr Wray reported receiving grants from the VA HSR&D during the conduct of the study. Ms Chapman reported receiving grants from VA HSR&D during the conduct of the study. Dr Kranzler reported receiving personal fees from Enthion, Sobrera Pharma, Sophrosyne Pharmaceuticals, American Society of Clinical Psychopharmacology’s ACTIVE Group supported by Alkermes, Dicerna Pharmaceuticals, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics, and Alcoholism: Clinical and Experimental Research and grants from Alkermes Pharmaceuticals outside the submitted work; in addition, Dr Kranzler had US Patent 10,900,082: “Genotype-guided dosing of opioid agonists, 26 Jan 2021 issued. Dr Gelernter reported receiving grants from the VA during the conduct of the study; having patent 10,900,082 issued; and receiving payment for editorial work for the journal Complex Psychiatry. Dr DuVall reported receiving grants from Alnylam Pharmaceuticals Inc, Astellas Pharma Inc, AstraZeneca Pharmaceuticals LP, Biodesix, Boehringer Ingelheim International GmbH, Celgene Corporation, Eli Lilly and Company, Genentech Inc, Gilead Sciences Inc, GlaxoSmithKline PLC, Innocrin Pharmaceuticals Inc, IQVIA Inc, Janssen Pharmaceuticals Inc, Kantar Health, MDxHealth, Merck & Co Inc, Myriad Genetic Laboratories Inc, Novartis International AG, and Parexel International Corporation outside the submitted work. Dr Lehmann reported being employed by Google and was employed by the VA when the study was developed and conducted. Dr Aslam reported receiving grants from the VA Research & Development during the conduct of the study. Dr Blow reported receiving grants from the VA during the conduct of the study and having stock ownership from Myriad Genetics outside the submitted work. Dr Brenner reported receiving grants from the VA, Department of Defense, National Institutes of Health (NIH), and the State of Colorado; editorial remuneration from Wolters Kluwer; and royalties from the American Psychological Association and Oxford University Press. In addition, she consults with sports leagues via her university affiliation. Dr Graham reported receiving grants from HSR&D (SDR 16-348, principal investigator: Oslin [04/2017-03/2022]) during the conduct of the study. Dr Hurley reported receiving grants from the VA during the conduct of the study and being employed by the VA. Dr J. A. Lynch reported receiving grants from the VA (HSR RES 13-457) during the conduct of the study, and grants from Alnylam Pharmaceutical, Astellas Pharmaceutical, AstraZeneca Pharmaceuticals, Biodesix, Boehringer Ingelheim, Celgene, Genentech, Janssen Pharmaceuticals, MDxHealth, Myriad Genetics, Novartis, and Paraxel outside the submitted work. Dr Ostacher reported receiving personal fees from Janssen (Johnson & Johnson) and Neurocrine and grants from Otsuka and Freespira (formerly Palo Alto Health Sciences Inc) outside the submitted work. Dr Voora reported receiving a donation to the VA, which supported clinical implementation of pharmacogenomics testing that indirectly provides salary support, from Sanford Health; grants from the NIH (site PI for the NIH IGNITE Network’s ADOPT-PGx trial of pharmacogenomics testing in depression), and personal fees from Optum Labs outside the submitted work. Dr Thase reported serving as an advisor/consultant for Acadia Inc, Akili Inc, Alkermes PLC, Allergan Inc, Axsome Therapeutics Inc, BioHaven Inc, Bocemtium Consulting SL, Boehringer Ingelheim International, CatalYm GmbH, Clexio Biosciences, Gerson Lehrman Group Inc, H. Lundbeck A/S, Jazz Pharmaceuticals, Janssen, Johnson & Johnson, Luye Pharma Group Ltd, Merck & Company Inc, Otsuka Pharmaceutical Company Ltd, Pfizer Inc, Sage Pharmaceuticals, Seelos, Sunovion Pharmaceuticals Inc, and Takeda Pharmaceutical Company Ltd; receiving grants from Acadia Inc, Allergan Inc, AssureRx Health, Axsome Therapeutics Inc, BioHaven Inc, Intracellular Inc, Johnson & Johnson, Otsuka Pharmaceutical Company Ltd, Patient-Centered Outcomes Research Institute, and Takeda Pharmaceutical Company Ltd; and receiving royalties from the American Psychiatric Foundation, Guilford Publications, Herald House, Kluwer-Wolters, and W.W. Norton & Company Inc; and his spouse’s employment with Peloton Advantage, which does business with most major pharmaceutical companies. No other disclosures were reported.

Figures

Figure.
Figure.. Screening, Enrollment, Randomization, and Outcomes Among Individuals in the Study of Antidepressant Pharmacogenomics
PHQ-9 indicates Patient Health Questionnaire–9; PTSD, posttraumatic stress disorder. aThe number of patients approached by clinicians was not collected.
See this image and copyright information in PMC

Comment in

References

    1. Stingl J, Viviani R. Polymorphism in CYP2D6 and CYP2C19, members of the cytochrome P450 mixed-function oxidase system, in the metabolism of psychotropic drugs. J Intern Med. 2015;277(2):167-177. doi:10.1111/joim.12317 - DOI - PubMed
    1. Rush AJ, Wisniewski SR, Warden D, et al. . Selecting among second-step antidepressant medication monotherapies: predictive value of clinical, demographic, or first-step treatment features. Arch Gen Psychiatry. 2008;65(8):870-880. doi:10.1001/archpsyc.65.8.870 - DOI - PubMed
    1. Trivedi MH, Rush AJ, Wisniewski SR, et al. ; STAR*D Study Team . Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40. doi:10.1176/appi.ajp.163.1.28 - DOI - PubMed
    1. Greden JF, Parikh SV, Rothschild AJ, et al. . Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: a large, patient- and rater-blinded, randomized, controlled study. J Psychiatr Res. 2019;111:59-67. doi:10.1016/j.jpsychires.2019.01.003 - DOI - PubMed
    1. Rothschild AJ, Parikh SV, Hain D, et al. . Clinical validation of combinatorial pharmacogenomic testing and single-gene guidelines in predicting psychotropic medication blood levels and clinical outcomes in patients with depression. Psychiatry Res. 2021;296:113649. doi:10.1016/j.psychres.2020.113649 - DOI - PubMed

Publication types

Substances

Associated data